The United States is currently facing an epidemic of methamphetamine (METH) abuse. METH abusers suffer from a variety of neurocognitive deficits, the pathophysiology of which remains poorly understood. In addition, the condition of many METH abusers is complicated by the co-occurrence of human immunodeficiency virus (HIV) infection. HIV infected patients who abuse drugs, including METH, have accelerated and more severe neurocognitive dysfunction compared with non-drug-abusing patients. Therefore, it is of paramount importance to determine the substrate underlying neurologic dysfunction in METH users infected with HIV. Only recently has it been recognized that neurogenesis continues through adulthood. Adult neurogenesis in the dentate gyrus (DG) of the hippocampus may play an important role in the long-term maintenance of cognitive function. We hypothesize that exposure to METH and expression of the HIV transactivator protein Tat disrupts neurogenesis by causing oxidative and nitrosative stress in neural progenitor cells (NPC). Preliminary studies suggest that both METH and Tat impair adult hippocampal DG neurogenesis in vivo; while METH has direct effects on NPCs, Tat's effects appear to be indirectly mediated. In the proposed studies, we will further characterize the cellular and molecular mechanisms by which this impairment occurs, focusing on oxidative and nitrosative stress as means by which HIV and METH disrupt neurogenesis. Additionally, we will investigate the potential of several therapeutic agents to protect against the combined effects of METH and HIV on neurogenesis. We will conduct our investigations using both cell culture and animal model systems. Ultimately, knowledge gained from these studies may assist in designing novel therapeutic strategies to combat the neurologic dysfunction in METH users and HIV-infected patients. Importantly, this proposal also includes a detailed career development plan. The Johns Hopkins Neurology Department provides a highly collaborative and interactive environment, exceptional expertise in neuro-AIDS and drug abuse research, and a host of educational opportunities. These factors, along with the guidance that I will receive in the laboratories of Drs. Avindra Nath and Hongjun Song, will grant me the opportunity to become a successful, independent clinician-scientist. [unreadable] [unreadable] [unreadable]